Cascade reaction

A cascade reaction, also known as a domino reaction or tandem reaction, is a chemical process that comprises at least two consecutive reactions such that each subsequent reaction occurs only in virtue of the chemical functionality formed in the previous step. In cascade reactions, isolation of intermediates is not required, as each reaction composing the sequence occurs spontaneously. In the strictest definition of the term, the reaction conditions do not change among the consecutive steps of a cascade and no new reagents are added after the initial step. By contrast, one-pot procedures similarly allow at least two reactions to be carried out consecutively without any isolation of intermediates, but do not preclude the addition of new reagents or the change of conditions after the first reaction. Thus, any cascade reaction is also a one-pot procedure, while the reverse does not hold true. Although often composed solely of intramolecular transformations, cascade reactions can also occur intermolecularly, in which case they also fall under the category of multicomponent reactions. A cascade reaction, also known as a domino reaction or tandem reaction, is a chemical process that comprises at least two consecutive reactions such that each subsequent reaction occurs only in virtue of the chemical functionality formed in the previous step. In cascade reactions, isolation of intermediates is not required, as each reaction composing the sequence occurs spontaneously. In the strictest definition of the term, the reaction conditions do not change among the consecutive steps of a cascade and no new reagents are added after the initial step. By contrast, one-pot procedures similarly allow at least two reactions to be carried out consecutively without any isolation of intermediates, but do not preclude the addition of new reagents or the change of conditions after the first reaction. Thus, any cascade reaction is also a one-pot procedure, while the reverse does not hold true. Although often composed solely of intramolecular transformations, cascade reactions can also occur intermolecularly, in which case they also fall under the category of multicomponent reactions. The main benefits of cascade sequences include high atom economy and reduction of waste generated by the several chemical processes, as well as of the time and work required to carry them out. The efficiency and utility of a cascade reaction can be measured in terms of the number of bonds formed in the overall sequence, the degree of increase in the structural complexity via the process, and its applicability to broader classes of substrates. The earliest example of a cascade reaction is arguably the synthesis of tropinone reported in 1917 by Robinson. Since then, the use of cascade reactions has proliferated in the area of total synthesis. Similarly, the development of cascade-driven organic methodology has also grown tremendously. This increased interest in cascade sequences is reflected by the numerous relevant review articles published in the past couple of decades. A growing area of focus is the development of asymmetric catalysis of cascade processes by employing chiral organocatalysts or chiral transition-metal complexes. Classificationof cascade reactions is sometimes difficult due to the diverse nature of the manysteps in the transformation. K. C. Nicolaou labels the cascades asnucleophilic/electrophilic, radical, pericyclic or transition-metal-catalyzed,based on the mechanism of the steps involved. In the cases in which two or moreclasses of reaction are included in a cascade, the distinction becomes ratherarbitrary and the process is labeled according to what can be arguablyconsidered the “major theme”. In order to highlight the remarkablesynthetic utility of cascade reactions, the majority of the examples below comefrom the total syntheses of complex molecules. Nucleophilic/electrophilic cascades aredefined as the cascade sequences in which the key step constitutes a nucleophilicor electrophilic attack. An example of such a cascade is seen in the short enantioselective synthesis of the broad-spectrum antibiotic (–)-chloramphenicol, reported by Rao et al. (Scheme 1). Herein, the chiral epoxy-alcohol 1 was first treated with dichloroacetonitrile in the presence of NaH. The resulting intermediate 2 then underwent a BF3·Et2O-mediated cascade reaction. Intramolecular opening of the epoxide ring yielded intermediate 3, which, after an in situ hydrolysis facilitated by excess BF3·Et2O, afforded (–)-chloramphenicol (4) in 71% overall yield. A nucleophilic cascade was also employed in the total synthesis of the natural product pentalenene (Scheme 2). In this procedure, squarate ester 5 was treated with (5-methylcyclopent-1-en-1-yl)lithium and propynyllithium. The two nucleophilic attacks occurred predominantly with trans addition to afford intermediate 6, which spontaneously underwent a 4π-conrotatory electrocyclic opening of the cyclobutene ring. The resulting conjugated species 7 equilibrated to conformer 8, which more readily underwent an 8π-conrotatory electrocyclization to the highly strained intermediate 9. The potential to release strain directed protonation of 9 such that species 10 was obtained selectively. The cascade was completed by an intramolecular aldol condensation that afforded product 11 in 76% overall yield. Further elaboration afforded the target (±)-pentalenene (12).